Potassium Phosphate, Tribasic → tert-butyl 4-(2-(2-(N-(5-fluorothiazol-2-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate

HRID 2172311Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 2172311
CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)O1.Br[C:34]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:35]=1[CH2:36][CH2:37][N:38]([S:44]([NH:47][C:48]1[S:49][C:50]([F:53])=[CH:51][N:52]=1)(=[O:46])=[O:45])[CH2:39]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O>[F:53][C:50]1[S:49][C:48]([NH:47][S:44]([N:38]2[CH2:37][CH2:36][C:35]3[C:40](=[CH:41][CH:42]=[CH:43][C:34]=3[C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:11][C:10]=3[C:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:21][CH:20]=3)[CH2:39]2)(=[O:46])=[O:45])=[N:52][CH:51]=1

Komponenten

7

Edukt 3

HCID 62657Potassium Phosphate, TribasicHCID 71259448tert-butyl 4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate2×HCID 898155775-bromo-N-(5-fluorothiazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide2×

Produkt 1

HCID 89815236tert-butyl 4-(2-(2-(N-(5-fluorothiazol-2-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylateAusbeute 25,9 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 962WaterLösungsmittelHCID 8857Ethyl AcetateLösungsmittelHCID 312751,4-DioxaneLösungsmittel

Versuchsvorschrift

A solution of Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 0.027 g, 0.038 mmol), tert-butyl 4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate K, 0.260 g, 0.574 mmol), 5-bromo-N-(5-fluorothiazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (Intermediate I, 0.150 g, 0.382 mmol), and potassium phosphate (0.325 g, 1.530 mmol) in 2.5 mL dioxane, 1 mL water was heated to 100° C. 2 hours. The reaction mixture was diluted with EtOAc and washed with 1 N citric acid solution. The organics were dried over MgSO4 and concentrated. Purification of the resulting residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave tert-butyl 4-(2-(2-(N-(5-fluorothiazol-2-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.063 g, 0.099 mmol). This material was taken up in 1 mL THF, was treated with HCl 4N in dioxane (1.912 ml, 7.65 mmol) and was allowed to stir at room temperature overnight. The reaction mixture was concentrated yielding N-(5-fluorothiazol-2-yl)-5-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride (0.063 g, 0.117 mmol). [M+H]+=538.8 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.82 (br. s., 2H), 7.73 (d, J=7.9 Hz, 1H), 7.60 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.30 (s, 1H), 7.25 (d, J=4.7 Hz, 2H), 7.02 (t, J=4.5 Hz, 1H), 5.71 (br. s., 1H), 4.29 (s, 2H), 3.62-3.68 (m, 1H), 3.53-3.59 (m, 2H), 3.37-3.44 (m, 1H), 3.18-3.28 (m, 2H), 2.85-3.07 (m, 2H), 2.06-2.20 (m, 1H), 1.92-2.02 (m, 1H)

Aufarbeitung

  1. custom2 hours
  2. washwashed with 1 N citric acid solution
  3. dry with materialThe organics were dried over MgSO4
  4. concentrationconcentrated
  5. customPurification of the resulting residue by silica gel column chromatography (0 to 100% EtOAc/heptane)

Quellen und Nachweise

ORD-Eintrag
ord-bd6a29a1db5e4245ae579c43efab0a4b
Quelldatensatz
uspto-grants-2015_06
Patentnummer
US09051311B2

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